Chronic inflammation is the cause and effect in the pathogenesis of endometriosis. Characterized as an imbalance of various kinds of cytokines and deficient immune-surveillance in the peritoneal cavity, endo- metriosis creates its own system to maintain the surviv- al of endometriotic cells outside of the uterus. Char- acteristics of the cells present in the microenvironment including immune cells and endometriotic cells have been changed by cytokines and other protein molecules, which are the critical keys that determine the develop- ment of the disease. In this review, we will focus on the effects from the inflammation-related factors on the phenotypic changes in cells in the pathogenesis of endo- metriosis to discuss.

Key Words: chronic inflammation, endometriosis, pro- inflammatory cytokines, prostaglandins

Introduction

Endometriosis is a gynecological disease that affects 8-10% of women of reproductive age (26, 30). It is characterized as the endometrial tissues growing outside of the uterine cavity, which cannot be elimi- nated by immune system (2). Patients suffered from the disease have clinical symptoms such as dysmen- orrhea, chronic pelvic pain, dyspareunia, and even infertility. Unfortunately, there is no effective way for curing the disease so far. The etiology of the disease is still not well established, but the theory developed by Sampson in 1927 is widely accepted by researchers (80). Sampson proposed the ectopic lesions are the tissues originated from endometrium that go toward other sites such as ovarian surface, peritoneum, urinary bladder or even colorectal sites through retrograde menstruation. With unclear mechanism, these endometriotic lesions successfully survive under the disadvantage microenvironment without being removed by the immune system. Con-

sequently, the microenvironment around is inclined to a state of chronic inflammation (69).

As mentioned before, the survival of these lesions may be due to the disability of the immune system (44, 74). For cancer or other chronically progressive diseases such as nephritis or some metabolic syn- dromes, chronic inflammation is basically involved, which the cytokines, chemokines or other small lipid mediators surrounding are important determinants for the establishment of this microenvironment. Similarly, in endometriosis, the small molecules and proteins may not only change the hormones regulation during the menstrual cycle, but also have the impact on the recruitment of some immune cells.

Herein, we focus on the relationship between the chronic inflammation and prostaglandins (PGs) and pro-inflammatory cytokines in the pathogenesis of endometriosis. We will summarize the molecular mechanisms involved in the pathophysiology of endometriosis and the critical factors that cause the progression of this disease.

PGs and Inflammation in the Pathogenesis of Endometriosis

PGs play essential roles in the states transition from acute inflammation to chronic one (8). PGs are a group of several kinds of lipid mediators such as PGD2, PGE2, PGF2, PGI2, and thromboxane A2 (TXA2). Through the binding of corresponding G-protein coupled receptors, they exert different effects on cell to maintain the physiological functions. Being studied involved in both acute and chronic inflammation (47, 61, 66), PGs were found to participate in T cells dif- ferentiation and also in various kinds of cytokines synthesis (20, 21, 40). It has also been demonstrated that PGs sustain inflammation by a positive feedback loop in endometriosis (100), which re-emphasizes

the important role of PGs in maintaining the relatively steady state in chronic inflammation.

Cyclooxygenases (COXs) are critical enzymes involved in the synthesis of PGs from arachidonic acids. Three isoforms of COX have been identified to date; COX-1, COX-2, and COX-3. COX-1 and COX-2 are two well characterized isoforms in physiological and pathological status. COX-1 is a constitutive enzyme, which means COX-1 mainly participates in the house-keeping process to catalyze arachidonic acid into PGs. In contrast, characterized as an inducible isoform, COX-2 shares similar protein structure with COX-1 but shows different expres- sion levels in various kinds of tissues and different responses to stimuli (60, 81, 97). COX-2 is known as an early response gene that reacts immediately to inducers such as growth factors, small molecules or lipid mediators (38). COX-2, instead of COX-1, is believed to take part in the pathogenesis of endo- metriosis (10, 23, 103). We had previously found that there are increasing levels of COX-2 in peritoneal macrophage in patients from mild to severe extent, which indicates that COX-2 level is related to the severity of the disease (103). Arosh et al. proved that COX-2 has functions to enhance the endometriotic cell proliferation, survival, and anti-apoptosis effect (10). Thus, the important role of COX-2 in the pathogenesis of endometriosis has already been es- tablished so far. Indeed, studies showed that treat- ment with selective COX-2 inhibitors significantly decreases size of the implanted lesions (52, 75).

Abundant expression of COX-2 in endometriosis is associated with the elevated PGE2 in peritoneal fluid in women with endometriosis (102). The major PGs produced by human endometrium are PGE2 and PGF2α (29, 86). Higher production of PGE2 and PGF2α were found in ectopic endometrium, which were thought to be correlated with the contraction of uterine smooth muscle and blood flow in patients with endometriosis (67, 99). One of the most important functions of PGs reported in endometriosis is to disable the normal function of macrophage. Although the findings show highly secreted cytokines (17, 78, 88), chemokines, recruitment of macrophages in peritoneal fluid in patients with endometriosis (28), it is reported the phagocytic function of these peritoneal macrophages are dysfunctional. Indeed, our previous study showed that PGE2 produced in patients cause the effect to weaken the phagocytic function of peritoneal mac- rophage through the inhibition of cluster of differ- entiation 36 (CD36) (24). In addition, our another study also showed PGE2 inhibits the expression level of annexin A2 in peritoneal macrophage via EP2/EP4 receptor-dependent downstream signaling, which will further reduce the phagocytic ability (101). On the other hand, besides to directly affect the phagocytic

function of phagocytes, PGE2 also suppresses the macrophage scavenger function of breaking down the extracellular matrix by inhibiting the expression level of matrix metalloproteinase 9 (MMP-9) (104). These studies provide the first solid evidence to demonstrate that inability to engulf retrograded endometrial debris by macrophage is due to PGE2- induced suppression of phagocytic capacity.

In addition to be a pain maker and phagocytosis reliever, PGE2 is also known to be a potential stimu- lator of steroidogenic genes (72, 90). Endometriosis is an estrogen-dependent disease. Ectopic endo- metriotic cells can generate estrogen themselves to maintain their own survival without depending on ovarian production, which explains why those cells still alive during menstrual phase instead of apoptosis (71, 72, 90). From previous studies, P450 aromatase and steroidogenic acute regulatory protein (StAR) play indispensable roles in de novo estrogen synthesis in endometriosis, which results in aberrant 17β- estradiol production (72, 90, 98). Both enzymes are not expressed in endometrial tissues of women without endometriosis, but highly expressed in patients with endometriosis (50, 71, 90). Furthermore, expression of the enzymes in patients with endo- metriosis is reported to be positively correlated with the severity of the disease (63). Previous studies demonstrated the different characteristics between ectopic stromal cells and eutopic ones are due to the effect of PGE2. That is, PGE2-induced aromatase alters the ectopic stromal cells to be more sensitive to PGE2, which can also explain why only ectopic stromal cells are responsive to PGE2 binding to produce StAR whereas the eutopic ones are not (90, 109, 114).

PGE2 also participates in promoting angiogenesis function. Direct correlation between PGs and an- giogenesis in endometriosis had been done in some research. Earlier study first unveiled the relationship in endometriosis from the observation. Kelly et al. found simultaneously elevated angiogenic factors, MMPs and PGs in the endometriotic fragments which are potential to facilitate the angiogenesis process

(15). Moreover, many studies done in different models have already proved the concept that biosyn- thetic pathway of COX-PGs promotes angiogenic activities through the regulation of angiogenic-related genes (7, 25, 32, 65, 76). In endometriosis study, Akoum et al. investigated that the higher level of

COX-2 and PGE2 in endometriotic lesions are regulated by the macrophage migration inhibitory factors (MIF), and the effect further enhances the angiogenic functions (18). In recent years, Pouliot et al.

demonstrated the PGF2α/FP receptor signaling pathway can activate the angiogenesis in endothelial cells directly via stimulating the production of potent angiogenic factors, vascular endothelial growth factor

(VEGF) and CXC chemokine ligand 8 (77). In another study, ectopic lesions harvested from mice treated with FP receptor antagonists showed decreased pattern of proliferation and endothelial cell markers than control groups (1).

In recent years, most of the studies focus on finding effective drugs to target PGE2. Through se- lective inhibition of PGE2 receptor EP2 and EP4 by antagonists or inhibitors in endometriotic cells (11), expression of downstream proteins matrix metal- lopeptidases (MMPs) and tissue inhibitor of metal- loproteinases (TIMPs) proteins responsible for tissue remodeling were found decreased in study from Arosh et al. (54). Jo Kitawaki et al. treated endo- metriotic stromal cells in vitro with dienogest (DNG),

afourth-generation progestin, and the results showed

successful inhibition of PGE2 and estrogen production (107). Arosh et al. found Thiazolidinediones (TZDs) can activate peroxisome proliferator-activated receptor

(PPAR) γ, and further inhibit the signaling of PGE2 by interfering with EP2 and EP4 (53). In vivo study has been done with EP2 antagonist, TG6-10-1 and PF-04418948, and the result showed successfully reduced hyperalgesia both in peripheral and central neuropathic pain in mice model (35).

Pro-Inflammatory Cytokines in Endometriosis

Peritoneal fluid from women with endometriosis consists of higher levels of cytokines that were sug- gested to be secreted by endometrial tissues, peri- toneal macrophages and other related immune cells (17, 45, 78, 88). Infiltration of activated leukocytes, particularly the peritoneal macrophage, is found around ectopic tissues, but they appear to be loss of function (36, 39). An imbalance situation of cytokines production is one of the main reasons why the lesions elimination by immunity is not successful. Therefore, component of cytokines around is extremely critical for determining defective immune-surveillance. The fluctuation of various kinds of cytokines have been monitored in endometriosis-induced model, which showed distinct patterns between each other (22). Additionally, cytokines enriched in peritoneal fluid also affect the gene expression of the cells incubated, which may promote cell survival or inhibit apoptosis. In the following, we will discuss about the functions and influences of certain cytokines that have been studied in endometriosis, including interleukins, MIF, and tumor necrosis factor α (TNF-α).

Interleukins

Interleukin-1β (IL-1β)

IL-1 is mainly secreted from immune cells such as

activated macrophages, neutrophils, T cells, and natural killer cells, and is reported to take part in in- nate immune response as well as the cell-mediated immunity (27). Among the 11 members of IL-1 family, IL-1β and IL-18 are the two most fully char- acterized, and IL-1β is the major cytokines found enriched in peritoneal fluid of women with endo- metriosis (85). From our previous study, higher ex- pression of COX-2 in ectopic endometrial tissue has been found to be induced by IL-1β, which further results in higher production of PGE2 in endometriosis (102). Furthermore, we have also demonstrated that IL-1β is one of the pro-inflammatory cytokines that upregulates the COX-2 expression in endometriosis via the regulation of miR-302a-mediated chicken ovalbumin upstream promoter transcription factor (COUP-TFII) (58). Whereas another study done by Yin et al. declared IL-1β mediated COX-2 is via extracellular signal-regulated Kinase (ERK) signal- ing pathway which further enhance the process of angiogenesis in endometriosis (42). It has also been demonstrated macrophage-derived IL-1β can induce the secretion of VEGF, MIF, monocyte chemotactic protein-1 (MCP-1), IL-6 and IL-8 from ectopic en- dometriotic cells (3, 9, 37, 41, 42, 94), which further enhances the cell survival and the development of the pathogenesis of endometriosis. It is also re- ported that macrophage-derived IL-1β can synergize with the local produced E2 to induce the secretion of a protein known as regulated upon activation, normal T cell expressed, and secreted (RANTES), which is able to increase the recruitment of more immune cells to the lesions site (4). Recently, Chen et al. has proved lipoxin A4 (LXA4), an endogenous molecule that may take part in the impairment of in- flammation in endometriosis identified by MALDI- TOF-MS, can diminish the migration and invasion abilities of endometriotic stromal cells induced by IL-1β (105), which also suggests the newly discov- ered protein is potential for the progression of endo- metriosis.

Interleukin-6 (IL-6)

Evidence showed elevated secretion of IL-6 was found in peritoneal fluid of patients with endo- metriosis when compared to disease-free women (71, 88, 91). In addition, it is reported that activated macrophages and stromal cells secrete similar levels of IL-6 (92), which suggests that there are altered gene expressions in endometriotic cells that change the cells phenotype which results in the pathogenesis of endometriosis. On the other hand, some research has also focused on the level of soluble IL-6 receptor, and Wu et al. has indicated expression of soluble IL-6 receptor in peritoneal fluid is increased with

the extent of severity of patients (56). Endometriotic cells-derived IL-6 has been demonstrated to be regulated by different kinds of inducers, such as IL-1, IL-10, and TNF-α (41, 79, 108). Terakawa et al. proved that TNF-α induces the IL-6 expression in endometriotic cells via the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway (108). Furthermore, the same group also found the TNF-α-induced IL-6 synthesis in endometriotic cells could be diminished by IL-10 through dephosphorylation of ERK1/2, c-Jun N-terminal kinase 1/2 (JNK1/2), and IκB (89). As for the functional role of IL-6 in endometriosis, there are some contradictory results due to the fact that early studies showed IL-6 exerts inhibitory or no effect on endometrial stromal cells growth (112, 113). However, study from Yoshioka et al. indicated endometriotic stromal cells are able to resist the IL- 6-mediated inhibitory effect (112). It has been con- cluded endometriotic cells may change their pheno- types into a state resisting to IL-6-inhibition, which results in the smoothly growth of the lesions. In addition to the effect on endometriotic cells, it has also been reported membrane-bound IL-6 receptor in peritoneal fluid is positioned on the surface of peri- toneal macrophages, which indicates macrophage is one of the main targets for IL-6 (56). Another study done by Davis et al. reported IL-6 decreased phagocytic function of peritoneal macrophages through the stimulation of increased endometrial haptoglobin secretion from endometriotic cells (83). Studies reported so far indicated highly expressed IL-6 may play a role to indirectly promote the endometriotic cell growth through the phenotype change of immune cells.

Interleukin-8 (IL-8)

IL-8 is a kind of chemokines which is also known as CXCL8. IL-8 is secreted by various kinds of immune cells, and is found higher level being synthesized by macrophages in peritoneal fluid from patients with endometriosis (78). However, synthesis of IL-8 is also found from endometriotic cells. Study from Arici et al. showed IL-8 is higher in eutopic endometrium in patients than disease-free ones, and also in ectopic epithelium when compared to normal endometrium (93). Moreover, Akoum et al. found the high con- centration of IL-8 secretion has no significant dif- ferences between different phases during the men- strual cycle, which further indicates the importance of IL-8 in the pathogenesis of endometriosis during the phase with scant supplements (5). Secretion of both macrophage-derived IL-8 and endometriotic IL-8 can be stimulated by some pro-inflammatory cytokines, such as IL-1β and TNF-α (6, 13, 14). In addition to being a chemoattractant, IL-8 is also an important

factor for promoting angiogenesis (12, 64), cell pro- liferation (55), anti-apoptosis (82), and cell adhesion (33). Cheerfully, Mueller et al. found gonadotropin- releasing hormone analogues (GnRHa) can success- fully downregulate the concentration of IL-8 in peri- toneal fluid of patients in previous study (70).

Macrophage MIF

As mentioned above, MIF induces the expression of COX-2 and PGE2, and further enhances the cell proliferation by activating angiogenic factors (18). Indeed, MIF is an potent mitogenic factor that origi- nally found liberated from immortalized human endothelial cells (110). Higher expression of MIF in endometriotic lesions from the early stage than advanced stages had been evaluated in previous study (46), which indicated that MIF plays the lead- ing role in the development of endometriosis during the highly active stage. Increased MIF expression in peritoneal fluid of women with endometriosis was reported to be induced by various sources. Akoum et al. proved that higher level of MIF in peritoneal fluid in patients is induced by macrophages-secreted IL-1β via the NF-κB regulation (16, 94). Lately, the same group unveiled that estrogen is another inducer for MIF, which was demonstrated by using receptor antagonist or agonist to manipulate the functions of estrogen receptor α (ERα) and ERβ in cells (95). In addition, MIF was found involved in the kinase signaling pathways. MIF plays an important role in activating p38 and ERK, which leads to the increase of ectopic endometrial implants (68, 111). Further- more, MIF was sown to participate in the synthesis of PGE2 through the p38 signaling pathway (18). Due to the indispensable role of MIF in endometriosis, it has been suggested to be a potential marker and promising target for curing the disease. Indeed, results from mice endometriosis model show that treatment with ISO-1, a kind of MIF antagonist, reduces the implanted lesions size, which, again, shows the important role of MIF in endometriosis (48, 73).

TNF-α

TNF-α was found to be elevated in the T lymphocytes in women with endometriosis than normal ones (87). It was suggested the function of TNF-α is related to the enhancement of regulatory T cells (Treg), a subset of T cells that modulate the immune system by exerting immunosuppressive effect in order to maintain the homeostasis, in endometriosis which may result in the increased survival and proliferation of the ectopic tissues. On the other hand, the secreted form of TNF-α found in peritoneal fluid are produced from various kinds of cell types including the endo-

metriotic cells themselves, peritoneal macrophages, neutrophils, natural killer cells and other immune cells (31, 43, 59, 78, 112). More specifically, Li et al. demonstrated TNF-α produced by endometrial stromal cells is stimulated by surrounding Treg-secreted TNF-α (96). Known for its driving function for angiogenesis (51, 57, 84), there are abundant studies focusing on this part to emphasize the importance of TNF-α in the development of endometriosis. Early studies have mentioned that TNF-α released by peritoneal macrophages is the key pro-inflam- matory cytokines promoting the angiogenesis and cell proliferation in the disease (59, 62). However, another study showed TNF-α enhances the prolif- eration of endometriotic cells indirectly via the in- duction of IL-8 protein expression (43). Recently, Mizunuma et al. reported peritoneal fluid- natural killer cells (pfNK) is another source of TNF-α secretion to facilitate cell proliferation (31). Fur- thermore, they also mentioned the lower expression of NKp46, which is one of the natural cytotoxicity receptors on NK cell surface, may be the cause of decreased NK cytotoxicity and elevated TNF-α production in endometriosis. Several therapeutic strategies have focused on targeting TNF-α down- stream pathway for the purpose of inhibiting the lesions growth. Thalidomide, inhibitor of NF-κB, and progestin such as norethisterone acetate (NETA), and dienogest (DNG) have been used to treat endo- metriotic stromal cells, and the results showed the successful inhibition of the IL-8 expression induced by TNF-α (34, 106). Interfering TNF-α downstream signaling with another potential NF-κB inhibitor, curcumin, also leads to similar inhibiting result (49). Experimentally block the pathway in vivo by using disulfiram, another kind of NF-κB and proteasome inhibitor, showed concentration of TNF-α is downreg- ulated, and both the growth and survival of implants were reduced (19). Another study showed significant decrease levels of VEGF, IL-6 and TNF-α in peritoneal fluid and serum in rat after treated with etanercept, an antagonist of TNF-α receptor (115).

Conclusions

PGs and cytokines greatly affect the immune cells and endometriotic cells in the pathogenesis of endometriosis. They not only change the characteristics of the cells involved, but also form a positive feedback loop to maintain their own “homeostasis” in the whole system. That may give a reasonable explanation for the high recurrence in patients after surgically removal of the lesion, which is another important issue to be discussed. Further advancement in knowing the extremely cru- cial role of chronic inflammation in the development of endometriosis is promising for clinical therapy by

targeting on inflammation effect.

Conflicts of Interest

All authors declare no conflict of interest.

References

1.Ahmad, S.F., Akoum, A. and Horne, A.W. Selective modulation of the prostaglandin F2alpha pathway markedly impacts on en- dometriosis progression in a xenograft mouse model. Mol. Hum. Reprod. 21: 905-916, 2015.

2.Ahn, S.H., Monsanto, S.P., Miller, C., Singh, S.S., Thomas, R. and Tayade, C. Pathophysiology and Immune Dysfunction in Endo- metriosis. Biomed. Res. Int. 2015: 795976, 2015.

3.Akoum, A., Jolicoeur, C. and Boucher, A. Estradiol amplifies interleukin-1-induced monocyte chemotactic protein-1 expression by ectopic endometrial cells of women with endometriosis. J. Clin. Endocrinol. Metab. 85: 896-904, 2000.

4.Akoum, A., Lemay, A. and Maheux, R. Estradiol and interleukin- 1beta exert a synergistic stimulatory effect on the expression of the chemokine regulated upon activation, normal T cell expressed, and secreted in endometriotic cells. J. Clin. Endocrinol. Metab.

87:5785-5792, 2002.

5.Akoum, A., Lawson, C., McColl, S. and Villeneuve, M. Ectopic endometrial cells express high concentrations of interleukin (IL)-8 in vivo regardless of the menstrual cycle phase and respond to oestradiol by up-regulating IL-1-induced IL-8 expression in vitro. Mol. Hum. Reprod. 7: 859-866, 2001.

6.Altan, Z.M., Denis, D., Kagan, D., Grund, E.M., Palmer, S.S. and Nataraja, S.G. A long-acting tumor necrosis factor alpha-binding protein demonstrates activity in both in vitro and in vivo models of endometriosis. J. Pharmacol. Exp. Ther. 334: 460-466, 2010.

7.Amano, H., Haysahi, I., Yoshida, S., Yoshimura, H. and Majima, M. Cyclooxygenase-2 and adenylate cyclase/protein kinase A signal- ing pathway enhances angiogenesis through induction of vascular endothelial growth factor in rat sponge implants. Hum. Cell. 15: 13-24, 2002.

8.Aoki, T. and Narumiya, S. Prostaglandins and chronic inflammation. Trends. Pharmacol. Sci. 33: 304-311, 2012.

9.Arici, A., Oral, E., Attar, E., Tazuke, S.I. and Olive, D.L. Monocyte chemotactic protein-1 concentration in peritoneal fluid of women with endometriosis and its modulation of expression in mesothelial cells. Fertil. Steril. 67: 1065-1072, 1997.

10.Banu, S.K., Lee, J., Speights, V.O., Jr., Starzinski-Powitz, A. and Arosh, J. A. Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mecha- nisms. Endocrinology 149: 1180-1189, 2008.

11.Banu, S.K., Lee, J., Speights, V.O., Jr., Starzinski-Powitz, A. and Arosh, J.A. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 induces apoptosis of human endometriotic cells through suppression of ERK1/2, AKT, NFkappaB, and beta-catenin pathways and activation of intrinsic apoptotic mechanisms. Mol. Endocrinol. 23: 1291-1305, 2009.

12.Barcz, E., Rozewska, E.S., Kaminski, P., Demkow, U., Bobrowska, K. and Marianowski, L. Angiogenic activity and IL-8 concentrations in peritoneal fluid and sera in endometriosis. Int. J. Gynaecol. Obstet.

79:229-235, 2002.

13.Bersinger, N.A., Frischknecht, F., Taylor, R.N. and Mueller, M.D. Basal and cytokine-stimulated production of epithelial neutrophil activating peptide-78 (ENA-78) and interleukin-8 (IL-8) by cultured human endometrial epithelial and stromal cells. Fertil. Steril. 89: 1530-1536, 2008.

14.Bersinger, N.A., Gunthert, A.R., McKinnon, B., Johann, S. and Mueller, M.D. Dose-response effect of interleukin (IL)-1beta,

tumour necrosis factor (TNF)-alpha, and interferon-gamma on the in vitro production of epithelial neutrophil activating peptide-78 (ENA-78), IL-8, and IL-6 by human endometrial stromal cells. Arch. Gynecol. Obstet. 283: 1291-1296, 2011.

15.Brenner, R.M., Nayak, N.R., Slayden, O.D., Critchley, H.O. and Kelly, R.W. Premenstrual and menstrual changes in the macaque and human endometrium: relevance to endometriosis. Ann. N. Y. Acad. Sci. 955: 60-74; discussion 86-68, 396-406, 2002.

16.Cao, W.G., Morin, M., Metz, C., Maheux, R. and Akoum, A. Stimulation of macrophage migration inhibitory factor expression in endometrial stromal cells by interleukin 1, beta involving the nuclear transcription factor NFkappaB. Biol. Reprod. 73: 565-570, 2005.

17.Cao, X., Yang, D., Song, M., Murphy, A. and Parthasarathy, S. The presence of endometrial cells in the peritoneal cavity en- hances monocyte recruitment and induces inflammatory cytokines in mice: implications for endometriosis. Fertil. Steril. 82 Suppl 3: 999-1007, 2004.

18.Carli, C., Metz, C.N., Al-Abed, Y., Naccache, P.H. and Akoum, A. Up-regulation of cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic cells by macrophage mi- gration inhibitory factor: involvement of novel kinase signaling pathways. Endocrinology 150: 3128-3137, 2009.

19.Celik, O., Ersahin, A., Acet, M., Celik, N., Baykus, Y., Deniz, R., Ozerol, E. and Ozerol, I. Disulfiram, as a candidate NF-kappaB and proteasome inhibitor, prevents endometriotic implant growing in a rat model of endometriosis. Eur. Rev. Med. Pharmacol. Sci.

20:4380-4389, 2016.

20.Chen, M., Boilard, E., Nigrovic, P.A., Clark, P., Xu, D., Fitzgerald, G.A., Audoly, L.P. and Lee, D.M. Predominance of cyclooxyge- nase 1 over cyclooxygenase 2 in the generation of proinflamma- tory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis. Arthritis Rheum. 58: 1354-1365, 2008.

21.Chen, Q., Muramoto, K., Masaaki, N., Ding, Y., Yang, H., Mackey, M., Li, W., Inoue, Y., Ackermann, K., Shirota, H., Matsumoto, I., Spyvee, M., Schiller, S., Sumida, T., Gusovsky, F. and Lamphier, M. A novel antagonist of the prostaglandin E(2) EP(4) receptor inhib- its Th1 differentiation and Th17 expansion and is orally active in arthritis models. Brit. J. Pharmacol. 160: 292-310, 2010.

22.Chen, Q.H., Zhou, W.D., Su, Z.Y., Huang, Q.S., Jiang, J.N. and Chen, Q.X. Change of proinflammatory cytokines follows certain patterns after induction of endometriosis in a mouse model. Fertil. Steril. 93: 1448-1454, 2010.

23.Chishima, F., Hayakawa, S., Sugita, K., Kinukawa, N., Aleemuz- zaman, S., Nemoto, N., Yamamoto, T. and Honda, M. Increased expression of cyclooxygenase-2 in local lesions of endometriosis patients. Am. J. Reprod. Immunol. 48: 50-56, 2002.

24.Chuang, P.C., Lin, Y.J., Wu, M.H., Wing, L.Y., Shoji, Y. and Tsai, S.J. Inhibition of CD36-dependent phagocytosis by prostaglandin E2 contributes to the development of endometriosis. Am. J. Pathol.

176:850-860, 2010.

25.Cianchi, F., Cortesini, C., Bechi, P., Fantappie, O., Messerini, L., Vannacci, A., Sardi, I., Baroni, G., Boddi, V., Mazzanti, R. and Masini, E. Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer. Gastroenterology 121: 1339-1347, 2001.

26.Cramer, D.W. and Missmer, S.A. The epidemiology of endometri- osis. Ann. N. Y. Acad. Sci. 955: 11-22; discussion 34-16, 396-406, 2002.

27.Dinarello, C.A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27: 519-550, 2009.

28.Dmowski, W.P., Steele, R.W. and Baker, G.F. Deficient cellular immunity in endometriosis. Am. J. Obstet. Gynecol. 141: 377-383, 1981.

29.Downie, J., Poyser, N.L. and Wunderlich, M. Levels of prostaglan- dins in human endometrium during the normal menstrual cycle. J. Physiol. 236: 465-472, 1974.

30.Eskenazi, B. and Warner, M.L. Epidemiology of endometriosis. Obstet. Gynecol. Clin. North. Am. 24: 235-258, 1997.

31.Funamizu, A., Fukui, A., Kamoi, M., Fuchinoue, K., Yokota, M., Fukuhara, R. and Mizunuma, H. Expression of natural cytotoxicity receptors on peritoneal fluid natural killer cell and cytokine pro- duction by peritoneal fluid natural killer cell in women with endo- metriosis. Am. J. Reprod. Immunol. 71: 359-367, 2014.

32.Gallo, O., Franchi, A., Magnelli, L., Sardi, I., Vannacci, A., Boddi, V., Chiarugi, V. and Masini, E. Cyclooxygenase-2 pathway correlates with VEGF expression in head and neck cancer. Implications for tumor angiogenesis and metastasis. Neoplasia 3: 53-61, 2001.

33.Garcia-Velasco, J.A. and Arici, A. Interleukin-8 stimulates the adhesion of endometrial stromal cells to fibronectin. Fertil. Steril. 72: 336-340, 1999.

34.Grandi, G., Mueller, M., Bersinger, N., Papadia, A., Nirgianakis, K., Cagnacci, A. and McKinnon, B. Progestin suppressed inflam- mation and cell viability of tumor necrosis factor-alpha-stimulated endometriotic stromal cells. Am. J. Reprod. Immunol. 76: 292-298, 2016.

35.Greaves, E., Horne, A.W., Jerina, H., Mikolajczak, M., Hilferty, L., Mitchell, R., Fleetwood-Walker, S.M. and Saunders, P.T. EP2 receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis. Sci. Rep. 7: 44169, 2017.

36.Haney, A.F., Muscato, J.J. and Weinberg, J.B. Peritoneal fluid cell populations in infertility patients. Fertil. Steril. 35: 696-698, 1981.

37.Herrmann Lavoie, C., Fraser, D., Therriault, M.J. and Akoum, A. Interleukin-1 stimulates macrophage migration inhibitory factor secretion in ectopic endometrial cells of women with endometriosis. Am. J. Reprod. Immunol. 58: 505-513, 2007.

38.Herschman, H.R. Prostaglandin synthase 2. Biochim. Biophys. Acta 1299: 125-140, 1996.

39.Hill, J.A., Faris, H.M., Schiff, I. and Anderson, D.J. Characteriza- tion of leukocyte subpopulations in the peritoneal fluid of women with endometriosis. Fertil. Steril. 50: 216-222, 1988.

40.Honda, T., Segi-Nishida, E., Miyachi, Y. and Narumiya, S. Prosta- cyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis. J. Exp. Med. 203: 325-335, 2006.

41.Hou, Z., Zhou, J., Ma, X., Fan, L., Liao, L. and Liu, J. Role of interleukin-1 receptor type II in the pathogenesis of endometriosis. Fertil. Steril. 89: 42-51, 2008.

42.Huang, F., Cao, J., Liu, Q., Zou, Y., Li, H. and Yin, T. MAPK/ ERK signal pathway involved expression of COX-2 and VEGF by IL-1beta induced in human endometriosis stromal cells in vitro. Int. J. Clin. Exp. Pathol. 6: 2129-2136, 2013.

43.Iwabe, T., Harada, T., Tsudo, T., Nagano, Y., Yoshida, S., Tanikawa, M. and Terakawa, N. Tumor necrosis factor-alpha promotes prolif eration of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J. Clin. Endocrinol. Metab. 85: 824-829, 2000.

44.Jeung, I., Cheon, K. and Kim, M.R. Decreased cytotoxicity of peripheral and peritoneal natural killer cell in endometriosis. Biomed. Res. Int. 2016: 2916070, 2016.

45.Kalu, E., Sumar, N., Giannopoulos, T., Patel, P., Croucher, C., Sherriff, E. and Bansal, A. Cytokine profiles in serum and perito- neal fluid from infertile women with and without endometriosis. J. Obstet. Gynaecol. Res. 33: 490-495, 2007.

46.Kats, R., Metz, C.N. and Akoum, A. Macrophage migration in- hibitory factor is markedly expressed in active and early-stage endometriotic lesions. J. Clin. Endocrinol. Metab. 87: 883-889, 2002.

47.Kawahara, K., Hohjoh, H., Inazumi, T., Tsuchiya, S. and Sugimoto, Y. Prostaglandin E2-induced inflammation: Relevance of prostaglan- din E receptors. Biochim. Biophys. Acta 1851: 414-421, 2015.

48.Khoufache, K., Bazin, S., Girard, K., Guillemette, J., Roy, M.C., Verreault, J.P., Al-Abed, Y., Foster, W. and Akoum, A. Mac-

rophage migration inhibitory factor antagonist blocks the develop- ment of endometriosis in vivo. PLoS One 7: e37264, 2012.

49.Kim, K.H., Lee, E.N., Park, J.K., Lee, J.R., Kim, J.H., Choi, H.J., Kim, B.S., Lee, H.W., Lee, K.S. and Yoon, S. Curcumin attenuates TNF-alpha-induced expression of intercellular adhesion molecule- 1, vascular cell adhesion molecule-1 and proinflammatory cytokines in human endometriotic stromal cells. Phytother. Res. 26: 1037- 1047, 2012.

50.Kitawaki, J., Noguchi, T., Amatsu, T., Maeda, K., Tsukamoto, K., Yamamoto, T., Fushiki, S., Osawa, Y. and Honjo, H. Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol. Reprod. 57: 514-519, 1997.

51.Kwon, Y.W., Heo, S.C., Jeong, G.O., Yoon, J.W., Mo, W.M., Lee, M.J., Jang, I.H., Kwon, S.M., Lee, J.S. and Kim, J.H. Tumor necrosis factor-alpha-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis. Biochim. Biophys. Acta 1832: 2136-2144, 2013.

52.Laschke, M.W., Elitzsch, A., Scheuer, C., Vollmar, B. and Menger, M.D. Selective cyclo-oxygenase-2 inhibition induces regression of autologous endometrial grafts by down-regulation of vascular endothelial growth factor-mediated angiogenesis and stimulation of caspase-3-dependent apoptosis. Fertil. Steril. 87: 163-171, 2007.

53.Lebovic, D.I., Kavoussi, S.K., Lee, J., Banu, S.K. and Arosh, J.A. PPARgamma activation inhibits growth and survival of human en-

dometriotic cells by suppressing estrogen biosynthesis and PGE2 signaling. Endocrinology 154: 4803-4813, 2013.

54.Lee, J., Banu, S.K., Subbarao, T., Starzinski-Powitz, A. and Arosh, J.A. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 inhibits invasion of human immortalized endometriotic epithelial and stromal cells through suppression of metalloproteinases. Mol. Cell. Endocrinol. 332: 306-313, 2011.

55.Li, M.Q., Luo, X.Z., Meng, Y.H., Mei, J., Zhu, X.Y., Jin, L.P. and Li, D.J. CXCL8 enhances proliferation and growth and reduces apoptosis in endometrial stromal cells in an autocrine manner via a CXCR1-triggered PTEN/AKT signal pathway. Hum. Reprod. 27: 2107-2116, 2012.

56.Li, S., Fu, X., Wu, T., Yang, L., Hu, C. and Wu, R. Role of Inter- leukin-6 and Its Receptor in Endometriosis. Med. Sci. Monit. 23: 3801-3807, 2017.

57.Ligresti, G., Aplin, A.C., Zorzi, P., Morishita, A. and Nicosia, R.F. Macrophage-derived tumor necrosis factor-alpha is an early component of the molecular cascade leading to angiogenesis in re- sponse to aortic injury. Arterioscler. Thromb. Vasc. Biol. 31: 1151- 1159, 2011.

58.Lin, S.C., Li, Y.H., Wu, M.H., Chang, Y.F., Lee, D.K., Tsai, S.Y., Tsai, M.J. and Tsai, S.J. Suppression of COUP-TFII by proinflam- matory cytokines contributes to the pathogenesis of endometriosis. J. Clin. Endocrinol. Metab. 99: E427-E437, 2014.

59.Lin, Y.J., Lai, M.D., Lei, H.Y. and Wing, L.Y. Neutrophils and macrophages promote angiogenesis in the early stage of endo- metriosis in a mouse model. Endocrinology 147: 1278-1286, 2006.

60.Liu, X.H. and Rose, D.P. Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines. Cancer Res. 56: 5125-5127, 1996.

61.Ma, X., Aoki, T., Tsuruyama, T. and Narumiya, S. Definition of Prostaglandin E2-EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth. Cancer Res. 75: 2822-2832, 2015.

62.Maas, J.W., Calhaz-Jorge, C., ter Riet, G., Dunselman, G.A., de Goeij, A.F. and Struijker-Boudier, H. A. Tumor necrosis factor-alpha but not interleukin-1 beta or interleukin-8 concentrations correlate with angiogenic activity of peritoneal fluid from patients with minimal to mild endometriosis. Fertil. Steril. 75: 180-185, 2001.

63.Maia, H., Jr., Haddad, C. and Casoy, J. Correlation between aro- matase expression in the eutopic endometrium of symptomatic pa- tients and the presence of endometriosis. Int. J. Womens. Health. 4:

61-65, 2012.

64.Medina, R.J., O’Neill, C.L., O’Doherty, T.M., Knott, H., Guduric- Fuchs, J., Gardiner, T.A. and Stitt, A.W. Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Mol. Med. 17: 1045-1055, 2011.

65.Mehrabi, M.R., Serbecic, N., Tamaddon, F., Kaun, C., Huber, K., Pacher, R., Wild, T., Mall, G., Wojta, J. and Glogar, H.D. Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease. Car- diovasc. Res. 56: 214-224, 2002.

66.Melgar, S., Drmotova, M., Rehnstrom, E., Jansson, L. and Mi- chaelsson, E. Local production of chemokines and prostaglandin E2 in the acute, chronic and recovery phase of murine experimental colitis. Cytokine 35: 275-283, 2006.

67.Moon, Y.S., Gomel, V., Yuen, B.H. and Nickerson, K.G. The role of prostaglandin F in the symptoms of endometriosis. Can. Med. Assoc. J. 129: 458-459, 1983.

68.Murk, W., Atabekoglu, C.S., Cakmak, H., Heper, A., Ensari, A., Kayisli, U.A. and Arici, A. Extracellularly signal-regulated kinase activity in the human endometrium: possible roles in the patho- genesis of endometriosis. J. Clin. Endocrinol. Metab. 93: 3532- 3540, 2008.

69.Ness, R.B. and Modugno, F. Endometriosis as a model for inflam- mation-hormone interactions in ovarian and breast cancers. Eur. J. Cancer 42: 691-703, 2006.

70.Nirgianakis, K., Bersinger, N.A., McKinnon, B., Kostov, P., Im- boden, S. and Mueller, M.D. Regression of the inflammatory microenvironment of the peritoneal cavity in women with endo- metriosis by GnRHa treatment. Eur. J. Obstet. Gynecol. Reprod. Biol. 170: 550-554, 2013.

71.Noble, L.S., Simpson, E.R., Johns, A. and Bulun, S.E. Aromatase expression in endometriosis. J. Clin. Endocrinol. Metab. 81: 174- 179, 1996.

72.Noble, L.S., Takayama, K., Zeitoun, K.M., Putman, J.M., Johns, D.A., Hinshelwood, M.M., Agarwal, V.R., Zhao, Y., Carr, B.R. and Bulun, S.E. Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J. Clin. Endocrinol. Metab.

82:600-606, 1997.

73.Nothnick, W.B., Colvin, A., Cheng, K.F. and Al-Abed, Y. Inhibition of macrophage migration inhibitory factor reduces endometriotic implant size in mice with experimentally induced disease. J. En- dometr. 3: 135-142, 2011.

74.Oosterlynck, D.J., Cornillie, F.J., Waer, M., Vandeputte, M. and Koninckx, P.R. Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium. Fertil. Steril. 56: 45-51, 1991.

75.Ozawa, Y., Murakami, T., Tamura, M., Terada, Y., Yaegashi, N. and Okamura, K. A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis xenografts via antiangiogenic activity in severe combined immunodeficiency mice. Fertil. Steril. 86: 1146-1151, 2006.

76.Pai, R., Szabo, I.L., Soreghan, B.A., Atay, S., Kawanaka, H. and Tarnawski, A.S. PGE(2) stimulates VEGF expression in endothe- lial cells via ERK2/JNK1 signaling pathways. Biochem. Biophys. Res. Commun. 286: 923-928, 2001.

77.Rakhila, H., Al-Akoum, M., Doillon, C., Lacroix-Pepin, N., Le- boeuf, M., Lemyre, M., Akoum, A. and Pouliot, M. Augmented Angiogenic Factors Expression via FP Signaling Pathways in Peritoneal Endometriosis. J. Clin. Endocrinol. Metab. 101: 4752- 4763, 2016.

78.Rana, N., Braun, D.P., House, R., Gebel, H., Rotman, C. and Dmowski, W.P. Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis. Fertil. Steril.

65:925-930, 1996.

79.Sakamoto, Y., Harada, T., Horie, S., Iba, Y., Taniguchi, F., Yoshida, S., Iwabe, T. and Terakawa, N. Tumor necrosis factor-alpha-induced interleukin-8 (IL-8) expression in endometriotic stromal cells,

probably through nuclear factor-kappa B activation: gonadotropin- releasing hormone agonist treatment reduced IL-8 expression. J. Clin. Endocrinol. Metab. 88: 730-735, 2003.

80.Sampson, J.A. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous cir- culation. Am. J. Pathol. 3: 93-110.143, 1927.

81.Sano, H., Kawahito, Y., Wilder, R.L., Hashiramoto, A., Mukai, S., Asai, K., Kimura, S., Kato, H., Kondo, M. and Hla, T. Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res.

55:3785-3789, 1995.

82.Selam, B., Kayisli, U.A., Garcia-Velasco, J.A., Akbas, G.E. and Arici, A. Regulation of fas ligand expression by IL-8 in human endometrium. J. Clin. Endocrinol. Metab. 87: 3921-3927, 2002.

83.Sharpe-Timms, K.L., Zimmer, R.L., Ricke, E.A., Piva, M. and Horowitz, G.M. Endometriotic haptoglobin binds to peritoneal macrophages and alters their function in women with endometriosis. Fertil. Steril. 78: 810-819, 2002.

84.Shin, M.R., Kang, S.K., Kim, Y.S., Lee, S., Hong, S.C. and Kim, E.C. TNF-alpha and LPS activate angiogenesis via VEGF and SIRT1 signalling in human dental pulp cells. Int. Endod. J. 48: 705-716, 2015.

85.Sikora, J., Mielczarek-Palacz, A. and Kondera-Anasz, Z. Imbal- ance in cytokines from interleukin-1 family - role in pathogenesis of endometriosis. Am. J. Reprod. Immunol. 68: 138-145, 2012.

86.Singh, E.J., Baccarini, I. and Zuspan, F.P. Levels of prostaglandins F-2alpha and E-2 in human endometrium during the menstrual cycle. Am. J. Obstet. Gynecol. 121: 1003-1006, 1975.

87.Szyllo, K., Tchorzewski, H., Banasik, M., Glowacka, E., Lewkowicz, P. and Kamer-Bartosinska, A. The involvement of T lymphocytes in the pathogenesis of endometriotic tissues overgrowth in women with endometriosis. Mediators Inflamm. 12: 131-138, 2003.

88.Tabibzadeh, S.S., Santhanam, U., Sehgal, P.B. and May, L.T. Cy- tokine-induced production of IFN-beta 2/IL-6 by freshly explanted human endometrial stromal cells. Modulation by estradiol-17β. J. Immunol. 142: 3134-3139, 1989.

89.Tagashira, Y., Taniguchi, F., Harada, T., Ikeda, A., Watanabe, A. and Terakawa, N. Interleukin-10 attenuates TNF-α-induced inter- leukin-6 production in endometriotic stromal cells. Fertil. Steril.

91:2185-2192, 2009.

90.Tsai, S.J., Wu, M.H., Lin, C.C., Sun, H.S. and Chen, H.M. Regu- lation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. J. Clin. Endocrinol. Metab. 86: 5765-5773, 2001.

91.Tseng, J.F., Ryan, I.P., Milam, T.D., Murai, J.T., Schriock, E.D., Landers, D.V. and Taylor, R.N. Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis. J. Clin. Endocrinol. Metab. 81: 1118- 1122, 1996.

92.Tsudo, T., Harada, T., Iwabe, T., Tanikawa, M., Nagano, Y., Ito, M., Taniguchi, F. and Terakawa, N. Altered gene expression and secretion of interleukin-6 in stromal cells derived from endometriotic tissues. Fertil. Steril. 73: 205-211, 2000.

93.Ulukus, M., Ulukus, E.C., Tavmergen Goker, E.N., Tavmergen, E., Zheng, W. and Arici, A. Expression of interleukin-8 and monocyte chemotactic protein 1 in women with endometriosis. Fertil. Steril.

91:687-693, 2009.

94.Veillat, V., Lavoie, C.H., Metz, C.N., Roger, T., Labelle, Y. and Akoum, A. Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation in- duced by interleukin- 1 beta in ectopic endometrial cells. Fertil. Steril. 91: 2148-2156, 2009.

95.Veillat, V., Sengers, V., Metz, C.N., Roger, T., Leboeuf, M., Mail- loux, J. and Akoum, A. Macrophage migration inhibitory factor is involved in a positive feedback loop increasing aromatase expres- sion in endometriosis. Am. J. Pathol. 181: 917-927, 2012.

96.Wang, X.Q., Zhou, W.J., Luo, X.Z., Tao, Y. and Li, D.J. Synergistic effect of regulatory T cells and proinflammatory cytokines in an-

giogenesis in the endometriotic milieu. Hum. Reprod. 32: 1304- 1317, 2017.

97.Wilborn, J., DeWitt, D.L. and Peters-Golden, M. Expression and role of cyclooxygenase isoforms in alveolar and peritoneal mac- rophages. Am. J. Physiol. 268: L294-L301, 1995.

98.Wing, L.Y., Chuang, P.C., Wu, M.H., Chen, H.M. and Tsai, S.J. Expression and mitogenic effect of fibroblast growth factor-9 in human endometriotic implant is regulated by aberrant production of estrogen. J. Clin. Endocrinol. Metab. 88: 5547-5554, 2003.

99.Witz, C.A. Current concepts in the pathogenesis of endometriosis. Clin. Obstet. Gynecol. 42: 566-585, 1999.

100.Wu, M.H., Shoji, Y., Chuang, P.C. and Tsai, S.J. Endometriosis: disease pathophysiology and the role of prostaglandins. Expert. Rev. Mol. Med. 9: 1-20, 2007.

101.Wu, M.H., Chuang, P.C., Lin, Y.J. and Tsai, S.J. Suppression of annexin A2 by prostaglandin E(2) impairs phagocytic ability of peritoneal macrophages in women with endometriosis. Hum. Re- prod. 28: 1045-1053, 2013.

102.Wu, M.H., Wang, C.A., Lin, C.C., Chen, L.C., Chang, W.C. and Tsai, S.J. Distinct regulation of cyclooxygenase-2 by interleukin- 1beta in normal and endometriotic stromal cells. J. Clin. Endo- crinol. Metab. 90: 286-295, 2005.

103.Wu, M.H., Sun, H.S., Lin, C.C., Hsiao, K.Y., Chuang, P.C., Pan, H.A. and Tsai, S.J. Distinct mechanisms regulate cyclooxygenase-1 and -2 in peritoneal macrophages of women with and without endo- metriosis. Mol. Hum. Reprod. 8: 1103-1110, 2002.

104.Wu, M.H., Shoji, Y., Wu, M.C., Chuang, P.C., Lin, C.C., Huang, M.F. and Tsai, S.J. Suppression of matrix metalloproteinase-9 by prostaglandin E(2) in peritoneal macrophage is associated with severity of endometriosis. Am. J. Pathol. 167: 1061-1069, 2005.

105.Wu, R.F., Yang, H.M., Zhou, W.D., Zhang, L.R., Bai, J.B., Lin, D.C., Ng, T.W., Dai, S.J., Chen, Q.H. and Chen, Q.X. Effect of interleukin-1beta and lipoxin A4 in human endometriotic stromal cells: Proteomic analysis. J. Obstet. Gynaecol. Res. 43: 308-319, 2017.

106.Yagyu, T., Kobayashi, H., Matsuzaki, H., Wakahara, K., Kondo, T., Kurita, N., Sekino, H., Inagaki, K., Suzuki, M., Kanayama, N. and Terao, T. Thalidomide inhibits tumor necrosis factor-alpha- induced interleukin-8 expression in endometriotic stromal cells, possibly through suppression of nuclear factor-kappa B activation. J. Clin. Endocrinol. Metab. 90: 3017-3021, 2005.

107.Yamanaka, K., Xu, B., Suganuma, I., Kusuki, I., Mita, S., Shimizu, Y., Mizuguchi, K. and Kitawaki, J. Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E(2) production in human endometriotic stromal cells in spheroid culture. Fertil. Steril. 97: 477-482, 2012.

108.Yamauchi, N., Harada, T., Taniguchi, F., Yoshida, S., Iwabe, T. and

Terakawa, N. Tumor necrosis factor-α induced the release of in- terleukin-6 from endometriotic stromal cells by the nuclear factor-

κB and mitogen-activated protein kinase pathways. Fertil. Steril. 82: 1023-1028, 2004.

109.Yang, S., Fang, Z., Suzuki, T., Sasano, H., Zhou, J., Gurates, B., Tamura, M., Ferrer, K. and Bulun, S. Regulation of aromatase P450 expression in endometriotic and endometrial stromal cells by CCAAT/enhancer binding proteins (C/EBPs): decreased C/EBPbeta in endometriosis is associated with overexpression of aromatase. J. Clin. Endocrinol. Metab. 87: 2336-2345, 2002.

110.Yang, Y., Degranpre, P., Kharfi, A. and Akoum, A. Identification of macrophage migration inhibitory factor as a potent endothelial cell growth-promoting agent released by ectopic human endome- trial cells. J. Clin. Endocrinol. Metab. 85: 4721-4727., 2000.

111.Yoshino, O., Osuga, Y., Hirota, Y., Koga, K., Hirata, T., Harada, M., Morimoto, C., Yano, T., Nishii, O., Tsutsumi, O. and Taketani, Y. Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis. Am. J. Reprod. Immunol. 52: 306-311, 2004.

112.Yoshioka, H., Harada, T., Iwabe, T., Nagano, Y., Taniguchi, F., Tan-

ikawa, M. and Terakawa, N. Menstrual cycle-specific inhibition of the proliferation of endometrial stromal cells by interleukin 6 and its soluble receptor. Am. J. Obstet. Gynecol. 180: 1088-1094, 1999.

113.Zarmakoupis, P.N., Rier, S.E., Maroulis, G.B. and Becker, J.L. Inhibition of human endometrial stromal cell proliferation by in- terleukin 6. Hum. Reprod. 10: 2395-2399, 1995.

114.Zeitoun, K.M. and Bulun, S.E. Aromatase: a key molecule in the

pathophysiology of endometriosis and a therapeutic target. Fertil. Steril. 72: 961-969, 1999.

115.Zulfikaroglu, E., Kilic, S., Islimye, M., Aydin, M., Zergeroglu, S. and Batioglu, S. Efficacy of anti-tumor necrosis factor therapy on endometriosis in an experimental rat model. Arch. Gynecol. Ob- stet. 283: 799-804, 2011.